Diltiazem, a benzothiazepine, is an orally active calcium channel blocker (calcium-antagonist) with relatively high selectivity for vascular smooth muscle that is effective in the treatment of hypertension and angina pectoris. Today, persons having these conditions take prescribed once daily preparations of Diltiazem generally to maintain constant levels of the drug in the body over a 24-hour period. Until recently the timing of the taking of the medicine wasn't considered an important consideration by the medical community. Doctors generally did not take into account the natural circadian variation in the body's physiological functions. Researchers have now found that the timing of the taking of a medicine can affect the way the human body responds to the medicine. The science of treating the human body taking into account the natural circadian variation is Chronotherapeutics. Chronotherapeutics relies on the practice of delivering the correct amount of medication to the correct site of action at the most appropriate time period for the particular disease or condition. In man, blood pressure does not remain constant during day and night. Early in the morning blood pressure begins to rise from the low levels reached during sleep. Increases in blood pressure are accompanied by increases in heart rate caused by the chemicals generated by the body and delivered into the blood stream. Epidemiological studies have indicated that the greatest incidence of heart problems such as stroke, heart attack, myocardial ischemia and sudden cardiac death occur during the early morning waking hours when the blood pressure is rising in response to the natural circadian rhythm. After normally rising in the morning, blood pressure remains elevated during the day until generally early evening when it starts to fall to its lowest level during sleep.
In one study, evening medication with Diltiazem for treatment of hypertension for effect the next morning has been stated to be more efficacious than other dosage schedules. Administration Time-Dependent Effects of Diltiazem on The 24-Hour Blood Pressure Profile of Essential Hypertension Patients, Isao Kohno et al. (Chronobiology International 14(1), 71–84, (1997.) In the report of the study, Herbesser R™ (200 mg) was identified as the Diltiazem preparation. Herbesser R™ is a Diltiazem formulation comprising a mixture of immediate release diltiazem—containing microspheres and sustained release diltiazem—containing coated microspheres. According to the report, following a single dose (200 mg) administration, the time of peak plasma diltiazem concentration occurred at 12.5 hours after administration. The peak plasma diltiazem concentration Cmax in the persons studied was 107 mg/ml. Following multiple dosages of 200 mg Diltiazem given over 7 days, the time of peak plasma diltiazem concentration (Cmax) was at 10 hours after administration. Cmax was 154 mg/ml.
However a careful review of the report shows inconsistencies which cannot support the authors' conclusions. Particularly at page 80, the best results shown in the graph are with respect to morning treatment with this formulation. Moreover at page 82, the authors themselves acknowledge the study cannot lead to reliable conclusions “because the number of patients was too small”. Further, an immediate release portion of the dosage in the order of 15% is not desirable for evening administration. When the blood pressure is naturally at its lowest, not only is there no need for further reduction at that time, but such reduction can harm the patient. Particularly, if the blood pressure is reduced below a minimum the patient is put at a greater risk for cardiovascular accidents including stroke. Further, the 15% immediate release diltiazem is no longer available when needed.
In A comparative study of the steady-state pharmacokinetics of immediate-release and controlled-release diltiazem tablets, O. R. Leeuwenkamp et al., Eur. J. Clin. Pharmacol (1994) 46:243–247, controlled release properties and relative systemic availabilities of two dosages of the same controlled release diltiazem tablet formulation were studied by comparing them as steady state with those of an immediate release formulation. In the testing, the diltiazem plasma concentration increased slowly from about 6 hours after the evening dose of both CR tablets (Diltiazem CR 90 mg and Diltiazem CR 120 mg) resulting in relatively high plasma concentrations in the early morning hours. The clinicians concluded that twice-daily treatment with diltiazem CR tablets can replace thrice-daily treatment with a conventional diltiazem IR tablet. According to the clinicians “The early morning rise of the diltiazem plasma concentration, which might lead to a lower incidence of ischemic events, may be an important clinical advantage of both CR tablets.”
On Apr. 22, 1998, Searle Canada announced that its Chronovera (R) (controlled onset extended-release verapamil) a high blood pressure medication was now available in Canada. Chronovera (R) was, according to Searle Canada, specifically designed to work with the body's natural circadian variations and was designed to be taken once-a-day just before bedtime. Chronovera provided 24-hour blood pressure control but was designed to deliver peak concentrations of verapamil in the morning when the blood pressure, heart rate and incidence of cardiovascular events were highest. According to Searle Canada, simply changing the time you take the drug your physician has prescribed will not provide the same safety and effectiveness that is designed specially for chronotherapy using verapamil. According to Searle Canada, its Chronovera (R) is unlike traditional medications including extended-release (XL) and sustained-release (SR) formulations which are usually prescribed in doses that maintain relatively constant levels of the drug in the body over a 24-hour period or attempt to maintain relatively constant levels of the drug in the body over a 24-hour period. According to Searle Canada, the prior formulations do not take into account the natural circadian variations in the body's physiological functions.
Sustained-release, once-daily diltiazem formulations have been taught which may be considered the traditional medication (according to Searle Canada). They appear not to give the benefits meant to be achieved by chronotherapy.
For example, in Pharmacokinetic Properties and Antihypertensive Efficacy of Once-Daily Diltiazem, J. G. Kelly et al., Journal of Cardio-Vascular Pharmacology, 17:6:957–963, (1991), the controlled-release formulation of diltiazem released a proportion of the diltiazem relatively rapidly with the remainder released over a period extending to 24-hours. During in vitro dissolution testing 15% of the diltiazem in the dosage form was released in the first two hours, 54% was released in the first six hours, 89% in the first 13 hours and all of the remainder was released between 13 and 24 hours after administration. The diltiazem capsules contained either 120 mg or 240 mg of diltiazem. It should be noted that no difference is shown between the placebo and dosages in the article at wake-up (between 5:00 a.m. and 8:00 a.m.).
U.S. Pat. No. 4,960,596 discloses slow release 12 hour diltiazem formulations whose dissolution, when measured in accordance with United States Pharmacopoeia 21, purports to be within broad limits (between 5% and 35% after one hour, between 15% and 40% after two hours, between 20% and 50% after three hours, between 30% and 75% after four hours, between 40% and 80% after six hours and between 55% and 95% after eight hours). The examples in the patent, however, provide more specific range limitations specifying range limitations for the formulations exemplified such as at column 4, lines 8–10 and column 5, lines 60–62. In the first series of examples the release into aqueous medium was measured using the method of USP No. 21 of 10%–20% after one hour, 30%–35% after four hours and 60%–75% after eight hours. In the later examples, the release into aqueous medium was measured using the method of USP No. 21 at 15%–35% after one hour, 55%–75% after four hours, 75%–95% after eight hours. These formulations were, however, twice a day (b.i.d.) formulations.
A series of patents have issued to Elan Corporation p.l.c. involving controlled absorption diltiazem pellet formulations for oral administration in which each pellet has a core comprising diltiazem or a pharmaceutically acceptable salt thereof in association with a specified organic acid covered by an outer membrane which permits release of diltiazem from aqueous medium in accordance with U.S. Pharmacopoeia XX (Paddle Method) in buffered media at pH 1.5, pH 4.0 and pH 7.0. These are U.S. Pat. Nos. 4,721,619; 4,891,230; 4,894,240; 4,917,899; 5,002,776; 5,219,621; 5,336,504; 5,364,620 and 5,616,345.
In U.S. Pat. No. 4,721,619, dissolution rates of the pellets of examples are found at column 4, lines 41–49 and column 5, lines 5–12. The formulations, however are for 12 hour. The formulations of U.S. Pat. No. 4,891,230 are also for administration every 12 hours.
U.S. Pat. No. 4,894,240 purports to provide formulations for once-daily administration and specifies a general dissolution pattern at column 2, lines 43–52 and a more restricted dissolution pattern at column 3, lines 3–12. The dissolution rates are determined according to U.S. Pharmacopoeia XXI in 0.05M KCl at pH 7.0 and at 100 r.p.m. The examples of the patent, however, provide a more limited dissolution pattern under U.S. Pharmacopoeia XXI (Paddle Method) at column 7, lines 30–34 and 47–51, at column 8, lines 16–20, 32–36 and 49–53 and at column 8, line 66—column 9, line 5. Similar examples are provided at columns 9, 10, 11 and 12. Nothing is taught with respect to formulations suitable as chronotherapeutics.
U.S. Pat. Nos. 4,917,899, 5,364,620 and 5,616,345 are to the same effect. So are the remaining Elan patents. Nothing in these patents teach formulations suitable as chronotherapeutics.
U.S. Pat. No. 5,529,790 purports to teach a delayed sustained-release pharmaceutical preparation in which a water-soluble drug core is surrounded by a hydratable diffusion barrier which delays drug release for about two to ten hours. While diltiazem hydrochloride dissolution patterns were provided in accordance with the U.S.P. basket dissolution method specified, no Cmax or the timing of the maximum blood levels is provided. The dissolution rates of the active are not appropriate for a suitable chronotherapeutic (see also U.S. Pat. Nos. 5,376,384 and 5,478,573).
U.S. Pat. Nos. 5,288,505 and 5,529,791 relate to extended-release galenical formulations of diltiazem or pharmaceutically acceptable salts thereof which comprise beads in which the active ingredient is in association with a wetting agent and which beads are coated by a microporous membrane. The Cmax of some formulations given in the patents provide for a Cmax after about 8–12 hours. Where the dosing of the formulations of the patents yields maximum diltiazem blood plasma levels (Cmax) of about 145 ng/ml, the Cmax is at about or less than 8 hours.
The applicants are also aware of a formulation marketed under the trade mark Tiazac™ a diltiazem HCl 24-hour sustained-release formulation based on teachings of U.S. Pat. Nos. 5,529,791 and 5,288,505.
Following chronic administration of Tiazac (240 mg once daily), the average peak plasma Diltiazem concentration (Cmax) is 183 ng/ml (multiple dosage) which occurred after about 7 hours past dose administration. Tiazac™ provides a bioavailability of approximately 59% of the total Diltiazem in the first 12 hours and 41% in the second 12 hours (after 12 hours, 59%; after 16 hours 77% and after 20 hours 90%).
In an article entitled Effect of Morning Versus Evening Dosing of Diltiazem on Myocardial Ischemia Detected by Ambulatory Electrocardiographic Monitoring in Chronic Stable Angio Pectoris, PRA KASH, C. Deedwanian et al., The American Journal of Cardiology, Vol. 80, Aug. 15, 1997, p. 421–425, the authors compare a.m. and p.m. dosing without using an appropriate dosage form for p.m. The Tmax is achieved between 2–6 hours at steady state.
In an article The Influence of Time Administration on the Pharmacokinetics of a Once A Day Diltiazem Formulation: Morning Against Bedtime, Jean Thiffault et al., Biopharmaceutics & Drug Disposition, Vol. 17, 107–115 (1996), the once-a-day diltiazem formulation given at 2200 hours for seven days gave according to the article “significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher”. The diltiazem dosages comprise 240 mg taken at 10:00 p.m. (22:00 hours) and maximum concentrations (Cmax) were achieved of 120 ng/ml after about six–eight hours of dosing. Unfortunately, the proposed system covers only the period from 2:00 a.m. to 8:00 a.m. To be a true chronotherapeutic, the time period covered should be between about 6:00 a.m. and noon. Moreover, this formulation when given at night leads to significantly lower bioavailability than if given in the morning.
It is therefore an object of this invention to provide diltiazem preparations suitable for once-a-day administration in the evening for providing effective dosage amounts in the blood of diltiazem in the morning when blood pressure begins to rise from the low levels reached during sleep, so as to be suitable as a chronotherapeutic preparation.
It is a further object of this invention to provide a method of administration of the diltiazem preparations suitable as a chronotherapeutic so as to be effective in the morning at a time when the patient has most need of the diltiazem preparation. Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed description of embodiments thereof.